Abstract
BackgroundRisk of normal tissue toxicity limits the amount of thoracic radiation therapy (RT) that can be routinely prescribed to treat non-small cell lung cancer (NSCLC). An early biomarker of response to thoracic RT may provide a way to predict eventual toxicities—such as radiation pneumonitis—during treatment, thereby enabling dose adjustment before the symptomatic onset of late effects. MicroRNAs (miRNAs) were studied as potential serological biomarkers for thoracic RT. As a first step, we sought to identify miRNAs that correlate with delivered dose and standard dosimetric factors.MethodsWe performed miRNA profiling of plasma samples obtained from five patients with Stage IIIA NSCLC at five dose-points each during radical thoracic RT. Candidate miRNAs were then assessed in samples from a separate cohort of 21 NSCLC patients receiving radical thoracic RT. To identify a cellular source of circulating miRNAs, we quantified in vitro miRNA expression intracellularly and within secreted exosomes in five NSCLC and stromal cell lines.ResultsmiRNA profiling of the discovery cohort identified ten circulating miRNAs that correlated with delivered RT dose as well as other dosimetric parameters such as lung V20. In the validation cohort, miR-29a-3p and miR-150-5p were reproducibly shown to decrease with increasing radiation dose. Expression of miR-29a-3p and miR-150-5p in secreted exosomes decreased with radiation. This was concomitant with an increase in intracellular levels, suggesting that exosomal export of these miRNAs may be downregulated in both NSCLC and stromal cells in response to radiation.ConclusionsmiR-29a-3p and miR-150-5p were identified as circulating biomarkers that correlated with delivered RT dose. miR-150 has been reported to decrease in the circulation of mammals exposed to radiation while miR-29a has been associated with fibrosis in the human heart, lungs, and kidneys. One may therefore hypothesize that outlier levels of circulating miR-29a-3p and miR-150-5p may eventually help predict unexpected responses to radiation therapy, such as toxicity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-016-0636-4) contains supplementary material, which is available to authorized users.
Highlights
Risk of normal tissue toxicity limits the amount of thoracic radiation therapy (RT) that can be routinely prescribed to treat non-small cell lung cancer (NSCLC)
Candidate miRNAs whose levels significantly correlated with RT dose, lung V5 and V20, mean lung dose and mean esophagus dose were identified. miRNA candidates identified in the screen were validated using samples from an additional NSCLC patients, collected before—and at 20 Gy
We identified two miRNAs that decreased in circulation with thoracic RT in patients with locallyadvanced NSCLC
Summary
Risk of normal tissue toxicity limits the amount of thoracic radiation therapy (RT) that can be routinely prescribed to treat non-small cell lung cancer (NSCLC). Factors that likely contribute to the high rate of locoregional failure include our inability to predict which patients may require dose escalation for local control or those who can tolerate higher doses to organs-at-risk. Prescriptions range between 60–70 Gy in 1.8 to 2.0 Gy fractions, depending on provider preferences and dosimetric constraints related to radiosensitive structures including the lungs, spinal cord, esophagus and heart [6]. Despite these constraints, 10–20 % of patients suffer moderate to severe radiation pneumonitis (RP) following standard treatment [7]. The RP-attributed mortality rate can be as high as 50 % [8]
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